The inner surface and capsule of joints are lined by a delicate vascular connective tissue known as the synovial membrane. In rheumatoid arthritis and related conditions, the membrane may become massively inflamed and thickened. The objectives of this study are to characterize these tissues in terms of the molecular mediators involved in generating the pathologic change. Over the past 2 years, we have been particularly interested in characterizing type 1 and type 2 cytokines during the earliest stages of synovitis (i.e., early synovitis). In a study of more than 200 synovial specimens from patients with new onset rheumatoid, reactive and undifferentiated arthritis, we demonstrated that cytokine profiles are skewed toward pro-inflammatory macrophage-derived and Th1 type cytokines such as TNF-alpha, IL-beta, IL-12 and IL-15. Interestingly, IL-2 and gamma interferon were more abundant in reactive arthritis relative to rheumatoid arthritis. IL-10 was also abundant in all patient groups and represented the major anti-inflammatory cytokine. IL-4 and IL-13 were rare. We also demonstrated that cytokine expression, as we expected, was highest in patients that were not treated with second-line drugs or corticosteroids (Kotake S et al., Proc. Assoc. Am. Phys. 109:286-302, 1997). In follow up studies, we have further evaluated cytokine expression in synovium of a subgroup of patients with Chlamydia-associated arthritis who were not treated with second-line drugs or corticosteroids. All of these patients had very high levels of both gamma interferon and IL-10 relative to other subgroups. We have speculated that the high levels of both a type 1 and type 2 cytokine may favor persistence of the organism in the joints (Kotake S et al., submitted for publication). Additional analysis is in progress on synovial specimens from normal volunteers.